A Long-Term Study of Sons of Alcoholics.

Men with a family history of alcoholism appear to have a lower intensity reaction to alcohol's effects than those without this family history. This study investigated whether a lower reaction could encourage greater alcohol consumption among family history-positive (FHP) subjects, predisposing them to develop alcohol-related problems. A family history of alcoholism was associated with increased risk of alcohol dependence and abuse among study subjects. Likewise, over half of the FHP's whose reactions to alcohol were low had developed alcoholism at a 10-year followup.

T he first step leading to the current investigation involving sons of al coholics was the recognition that alcoholism (usually meaning alcohol dependence 1 ) was likely to be genetically influenced. By 1970 it was apparent to re searchers that alcoholism runs strongly in families, and studies of twins demonstrated that a higher risk for this disorder is associ ated with a greater level of genetic closeness to an alcoholic person 2 (Schuckit 1994a). In acknowledgment of this important earlier work, several studies demonstrated that the risk for alcoholism in a person is best predicted by severe alcohol problems in a biological parent, not by the pattern of problems in an adoptive or rearing parent (Goodwin et al. 1973;Schuckit et al. 1972). (For further discussions of twin and adoption studies, see the articles by Cadoret,and Prescott and Kendler, The studies from the early 1970's also revealed how complex the genetic influ ences in alcoholism are likely to be. It became apparent that the mode of inheri tance of alcoholism does not follow any 1 As it is used in this article, the term "alcoholism" refers to the definition of alcohol dependence stated in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition. 2 Identical twins have the same genetic makeup. There fore, they possess greater genetic closeness than do fraternal twins. simple single gene but is more likely to involve multiple genes or a limited amount of genetic material that is not always ex pressed. The twin and adoption studies also affirmed that genes are unlikely to be the sole cause of alcoholism. Instead, they appear to interact with environmental events to produce a higher or lower level of risk. These investigations also revealed that it is likely that many different ways exist for a person to be genetically at higher or lower risk for alcohol depend ence (Schuckit 1994a).

STUDY PREPARATIONS
In 1975, in response to these complexities, preliminary studies were begun to determine whether it was possible to identify some genetic factors that interact with the envi ronment to increase the risk for severe alcoholrelated problems over the life span. The plan first called for a comparison of family historypositive (FHP) subjects (i.e., relatives of alcoholics) with family historynegative (FHN) controls. The research group began by hypothesizing that people at higher and lower risk for alcoholism may differ in their personality structure, their cognitive or thinking styles, or their reactions to alcohol. The latter idea grew out of reports from patients that from early on in their drinking careers, they had been able to consume large amounts of alcohol with relatively little effect. As described in other papers (Schuckit 1994a), the research group conjectured that a lower intensity of reaction to alcohol might en courage some people to consume greater amounts during most drinking sessions. This pattern, in turn, could make such people more likely to develop alcohol related life problems. Subsequently, the research group hoped that if it identified differences between FHP's and FHN's, particularly with respect to alcohol reac tion intensity, it would be able to follow up with the subjects a decade or so later to see whether those earlier differences pre dicted who developed alcoholism (Schuckit 1994a). This article briefly reviews the results of this ongoing investigation.

THE RESEARCH APPROACH
After the preliminary studies helped to im prove research methods, a questionnaire was used each year from 1978 to 1988 to identify Caucasian males between ages 18 and 25 who drank but who were not alco hol dependent. Those men who reported problems consistent with alcoholism in their biological fathers were selected as the FHP's, or highrisk subjects. For each FHP, an FHN (with no family history of alcoholism) was selected based on similar ity with respect to age; race; educational level; and pattern of alcohol, tobacco, marijuana, and other drug use. The simi larity of drinking patterns was important to ensure that any FHP-FHN differences in the reaction to alcohol were not just a reflection of differences in early drinking practices. To avoid any possible impact of fetal alcohol syndrome, the subjects se lected had an alcoholic father but not an alcoholdependent mother.
All subjects were brought to the labora tory, where facetoface interviews were conducted to verify the subjects' family histories and drinking status, and person ality and cognitive tests were administered. All subjects then received a dose of alcohol ranging from approximately three to five drinks (0.75 to 1.1 mL of ethanol per kg of body weight). In an additional session, all but the earliest group of subjects (because the study had not yet been refined) received a placebo, believing that they had been given alcohol. After consuming the bever ages, the subjects' biological and perceptual changes were evaluated over the next 3 hours. These postdrink measures, recorded every 15 to 30 minutes, included evalua tions of the subjects' own feelings of intox ication; evaluations of the more biological changes associated with drinking (such as alcoholrelated alterations in hormones and brain waves); and changes in motor perfor mance, using body sway as an indicator (Schuckit and Gold 1988;Schuckit 1994a). Between 1978 and, the reactions to alcohol were evaluated for 453 men. Subsequently, between 1989 and 1994, when the subjects were about 30 years old, steps were taken to locate them. The goal was primarily to determine the relationship between the subjects' intensity of reaction to alcohol (defined by the combination of their subjective feelings and biological changes following an alcohol challenge) and their future risk for alcoholrelated problems (Schuckit 1994a,b;Schuckit et al. 1994  and family history-negative (FHN) subjects before consuming alcohol (i.e., at baseline [BA]) and at points during the 3 hours after receiving 1.1 mL/kg of alcohol (equal to four or five drinks). As shown here, FHP subjects experienced a lesser change in cortisol levels than did FHN subjects, demonstrating the FHPs' lower levels of response to alcohol.

FHN FHP
were carried out by researchers who knew nothing about the subjects' statuses at age 20. To corroborate the information provided by the subjects, an interview was carried out with an additional informant (usually the spouse), and blood tests (indicators of whether heavy drinking had recently oc curred) and urine samples for drug toxicol ogy screens were obtained (Schuckit 1994b).

Comparing Populations
Despite a clear family history of alcoholism in one group and no family history of severe alcohol problems in the other, the FHP's and FHN's demonstrated no consis tent differences on personality measures (Schuckit et al. 1994). Nor were any differ ences observed on cognitive test results in the group of FHP's and FHN's matched with respect to educational level (Schuckit 1994a;Schuckit et al. 1987a;Schuckit et al. 1990). Following the alcohol challenges, the FHP's and the control group also had virtually identical blood alcohol concentra tions during the 3hour testing session (Schuckit and Gold 1988;Schuckit 1994a). This result was consistent with the manner in which the two family history groups had been carefully matched in their usual drink ing patterns and druguse histories. Despite the similarities between FHP's and FHN's, approximately 40 percent of the sons of alcoholics but fewer than 10 percent of the control subjects demonstrated remarkably low levels of reaction to the al cohol they were given (Schuckit and Gold 1988). Figure 1 depicts one example of this finding using a biological measure-the changes in the hormone cortisol following the alcoholconsumption challenge (Schuckit et al. 1987b). Cortisol level, however, is only one measure. Similar types of FHP-FHN differences, each demonstrating a lower level of response to alcohol among the sons of alcoholics, were shown for subjective feelings of intoxication, levels of standing steadiness (i.e., body sway), two additional hormones, and two different measures of brain activity (Schuckit 1994a).

Followup
Having demonstrated a lower level of re sponse to alcohol among the sons of alco holics across different alcohol doses and using different measures over the years, the next step involved the followup. As described in more detail in several recent publications (Schuckit 1994a,b; Smith in press), all 453 men were success fully located an average of 8.3 years follow ing their initial testing. Almost all these subjects (i.e., 450 of 453 men, or 99.3 per cent) participated in the followup evaluation, which involved a facetoface interview with each subject and with an additional informant, such as a spouse. As reported in a recent manuscript, focusing on the men for whom a family history could be clearly established (e.g., after excluding FHN subjects for whom alcohol problems developed in a more distant relative during the followup), a family history of alcoholism was associated with an almost threefold in creased risk for alcohol dependence and at least a doubling of the rate for alcohol abuse (Schuckit and Smith in press). At the same time, the FHP's had no marked increased risk for abuse of or dependence on marijuana type drugs (i.e., cannabinols), although they showed a trend for increased risk for stimu lant abuse or dependence. Sons of alcoholics had no higherthanexpected rates of psy chiatric disorders (except for alcoholism). The latter finding argues against the possi bility that the subjects who went on to develop alcoholism might have been selfmedicating a psychiatric problem.
The results of the major focus of the study-the relationship between the level of response to alcohol early in life and the future risk for alcoholism-were fairly clear. Analysis of the data from the first 223 sub jects revealed that 56 percent of the FHP's with lower levels of alcohol response devel oped alcoholism during the period before followup, compared with only 14 percent of those with high levels of sensitivity to alco hol (Schuckit 1994b). Figure 2 presents data from the sample of more than 400 men who could be clearly classified regarding family history, comparing the reactions to alcohol at about age 20 for those men who later developed alcoholism with the reac tions for the men who did not. The data reveal a much lower response to alcohol for the men who later developed alcohol abuse or dependence. It appears that at least among the subjects who had very high or very low levels of response to alcohol early in life, much of the family history's ability to predict future alcoholism appeared to operate through this level of response to alcohol (Schuckit and Smith in press).

Figure 2
Responses to alcohol (Z scores) were compared for 424 subjects who were followed for more than 8 years to monitor whether they developed alcoholism. Z scores show how far a subject's reaction to alcohol differs from the average response. Levels of reactions were based on subjective reports and changes in body sway and the hormone cortisol. Those who later developed alcoholism had much lower Z scores at their peak blood alcohol concentrations and at subsequent time points, D1 and D2, than those who did not develop alcoholism. 1 1 Only subjects for whom all relevant data were available were included.

PUTTING THESE FINDINGS IN PERSPECTIVE
This longterm study of Caucasian men at high and low risk for alcoholism suggests several conclusions. First, the data reaffirm how important family history is in predict ing future alcoholism. Second, the level of response to alcohol at approximately age 20 is both significantly lower among men at high risk for developing this disorder (i.e., sons of alcoholics) and appears, by itself, to be a fairly potent predictor of future alcoholism risk. Thus, both FHP's and FHN's with the lower level of response to alcohol had high rates of subsequent al cohol abuse or dependence. Third, these data do not indicate that (at least for this sample of 450 relatively functional young men) the future risk for alcoholism is re lated to any higher risk for the development of a major psychiatric disorder (such as se vere depressive episodes or severe anxiety) before the onset of alcoholism. Finally, the most recent analyses indicate that for those individuals with extreme levels (i.e., very high or very low) of response to alcohol, much of the family history's ability to pre dict the future risk for alcoholism relates to the low level of response to alcohol.

New Research Directions
At the same time, these study results dem onstrate how complex the risk for alco holism seems to be. For example, some men who showed the low response did not de velop severe problems with alcohol. Thus, for the 15year followup of these same subjects, the research group is gathering information about environmental and psy chological factors that may interact with the level of response to alcohol to help protect people who are at risk for alcohol abuse or dependence. Some of the additional factors being studied include levels of life stress, ways of coping with stress, and drinking and drug use by peers. Identifying protec tive environmental, interpersonal, and other factors that interact with biological influ ences is a major goal of the current work.
This ongoing stage of followup also will allow the research group to observe an important population of women as well as men. Additional information is therefore being gathered about the sons and daugh ters of the original subjects (i.e., the grandchildren of alcoholics).
Of course, the studies described here evaluate only one part of the picture. Some men and women develop alcohol problems while in their teens, often in the context of severe and repeated antisocial problems. Such subjects were not included in this in vestigation. Other alcoholdependent people may have developed their disorder in asso ciation with schizophrenia or another severe psychiatric disorder; these people were not included in this work if they had experi enced an early onset of their psychiatric problem. The finding that the majority of al coholics do not have severe psychiatric dis orders, however, is consistent with additional studies from this research group (although alcoholics do demonstrate temporary psychi atric problems in the context of their intoxi cation or withdrawal) (Schuckit 1994a).
The studies described here also are limited to Caucasian and moderately func tional subjects who had jobs or were in school when originally selected. To deter mine if similar results could be seen in an other group of people, the findings recently have been replicated in a totally different sample of children of alcoholics selected as part of the research for the Collabora tive Study on the Genetics of Alcoholism (Schuckit et al. in press). This group is more racially diverse and includes male and fe male subjects from all parts of the country.
The potential importance of a low level of response to alcohol has been corroborated by a recent overview, or metaanalysis, of studies comparing FHP's and FHN's (Pollock 1992). At the same time, other studies-often using different alcohol doses, different modes of administering alcohol over an extended period of hours, or addi tional challenges during the test session (such as electric shock)-do not always show the same results as those reported here (Newlin and Thomson 1991;Bauer and Hesselbrock 1993). Impressive work from other laboratories also indicates that additional biological factors, such as brain waves, might be associated with enhanc ing future alcoholism risk (Begleiter and Porjesz 1988).

SUMMARY
This article has reported data from a series of studies that span the period from 1970 to 1995. These investigations support the importance of genetic influences in alco holism but emphasize that subgroups of alcoholics exist whose disorder reflects different genetic and environmental fac tors. One of many potential characteristics that might increase the probability that a person will drink more heavily and more often is a lower level of intensity of reac tion to alcohol. Some people may there fore develop alcoholrelated problems because they seek a response to alcohol that they can only perceive at higher levels of alcohol intake, a pattern that in itself increases the probability of the need for evergreater amounts of alcohol and sub sequent alcoholrelated problems. ■